Monday, September 15, 2008

Colon Cancer Oncogene Discovered

(HealthDay News) -- Researchers have identified a new genetic player in the development of colon cancer.

The findings implicate CDK8, a protein that regulates gene expression in the proliferation of colorectal cancer, the researchers found.

Should the results be validated, they could lead to new therapeutic approaches for colon cancer, as well as new screening and chemopreventative strategies, said Dr. Durado Brooks, director of prostate and colorectal cancer at the American Cancer Society.

"I think it is important work," Brooks said. "They have identified what apparently is an oncogene associated with some colorectal cancers."

Dr. William Hahn, of the Dana-Farber Cancer Institute in Boston, and his colleagues screened human colon cancer cells for genes that met three criteria: They were required for cellular proliferation, critical to regulating the WNT/beta-catenin signaling pathway known to be involved in the bulk of colon cancer cases, and also genetically amplified in cancerous cells.

"When we did that, we found one gene that fulfilled all three criteria, and that is CDK8," Hahn said.

The results were published in the Sept. 14 issue of Nature.

CDK8 is a member of the so-called mediator complex, which bridges distant protein complexes to activate expression of certain genes.

According to Hahn, the study has two take-home messages.

The first, he said, is the apparent prevalence of colorectal tumors with elevated CDK8. Of the 50 tumors that Hahn and his team analyzed, 31 (62 percent) displayed evidence of CDK8 gene amplification -- that is, the tumors contained more than the normal two copies of the gene, which usually leads to higher levels of protein expression.

"This is surprising in the sense that it occurs in a large percentage of colon cancers, and we didn't know about it," he said.

The second message involves the potential pharmacologic benefits of these results. CDK8 is a type of protein known as a kinase. Kinases are enzymes that catalyze the transfer of phosphate groups from one molecule to another. That action is like flipping a molecular switch, causing the recipient protein to turn on or off. It turns out that kinases tend to play key roles in the biochemical pathways that often go haywire in cancer, so they are popular targets for drug developers.

"There's a reasonable likelihood, though it hasn't happened yet, that one could develop a drug that targets this protein in colon cancer," he said, "and you could determine which colon cancer patients are likely to benefit."

That's because Hahn and his team showed, using a genetic technique called RNA interference, that knocking down CDK8 protein levels in cancer cells that normally contain elevated CDK8 levels, reduced cell proliferation. That effect was less pronounced in cells containing lower levels of CDK8.

So, those tumors with elevated CDK8 levels might make good candidates for novel drug therapies directed at the enzyme, Hahn said.

"This fits into an emerging concept in cancer treatment," he explained. "Not only do we develop better therapies, but hand-in-hand, we want to find which patients will respond to therapy, rather than giving it to everyone and hoping they will respond."

Brooks agreed that CDK8 is a potential drug target. He noted other potential benefits, too, such as possibly being able to identify those at elevated risk of developing colorectal cancer, or identifying those who should be screened earlier and more comprehensively. It may even be possible to develop chemopreventative compounds that could diminish the risk of developing cancer in the first place.

"But we are at the very beginning of that pathway," Brooks added. "All they have shown is this oncogene seems to be associated with a significant number of cancer specimens.... But translating that to, number one, how broadly this occurs in the broader community of colorectal cancer, and also in the general patient population, and then next, how can we use this information, we are at the very beginning of that process."

In another report in this week's online issue of Nature Genetics, researchers from Iceland said that they have found a genetic variant associated with increased risk of urinary bladder cancer.